Synthesis for the preparation of tetracyclic compounds

ABSTRACT

The invention relates to a new synthesis for the preparation of tetracyclic compounds of the general formula: ##STR1## as well as the pharmaceutically acceptable salts thereof, in which: N IS THE NUMBER 1 OR 2, 
     m is the number 1, if n = 2 and the number 2, if n = 1, 
     R 1  and R 2  stand for hydrogen, hydroxy, halogen, lower alkyl (1-4 C), lower alkoxy (1-4 C) or trifluoromethyl and 
     R 3  represents hydrogen, alkyl (1-6 C), aralkyl (7-10 C) or an amino alkyl group (1-6 C), in which the nitrogen atom has been substituted by two alkyl groups (1-4 C), or the nitrogen atom forms part of a heterocyclic 5- or 6-membered ring, 
     Having valuable biological properties.

The invention relates to a new synthesis for the preparation oftetracyclic compounds of the general formula: ##STR2## as well as thepharmaceutically acceptable salts thereof, in which: N IS THE NUMBER 1OR 2

m is the number 1, if n= 2 and the number 2, if n= 1.

R₁ and R₂ stand for hydrogen, hydroxy, halogen, lower alkyl (1-4 C),lower alkoxy (1-4 C) or trifluoromethyl and

R₃ represents hydrogen, alkyl (1-6 C), aralkyl (7-10 C) or an aminoalkylgroup (1-6 C), in which the nitrogen atom has been substituted by twoalkyl groups (1-C), or the nitrogen atoms forms part of a heterocyclic5- or 6-membered ring.

The tetracyclic compounds according to the general formula I are knowncompounds, described i.a. in the Dutch Pat. No. 129,434 and the Dutchpatent application No. 72,12,915. They have very valuable biologicalproperties, especially antiserotonin, antihistamine and antidepressantactivities.

Up to now the compounds I have been prepared starting from the tricyclicdibenzo-azepine derivatives of the general formula II: ##STR3## in whichn, R₁, R₂ and R₃ have the aforesaid meaning.

The starting product II was converted into the final product accordingto formula I in one step by means of a condensation with, for instance,dihaloethane (m= 2), formaldehyde (m= 1), and methylene halide (m= 1),or in two steps by means of a condensation with, for instance,diethyloxalate (m= 2), monochloro-acetyl-chloride (m= 2),ethylchloroformate (m= 1), or phosgene (m= 1), followed by a reductionof the keto group(s) of the compound thus obtained.

However, these known syntheses do not proceed in a way that issatisfactory in every respect. In practice the "two-steps" condensationreaction appears to be less suitable for production on a large scale,while the "one-step" condensation reaction, particularly in the case ofcompounds I with n=1 and m= 2, does not always result in equallyconstant yields.

Main objection to these conventional syntheses is, however, the factthat the preparation of the required starting material II is a verytime-consuming, multiple-step synthesis which in general gives very pooryields.

The preparation of the starting material II, for instance, in which R₁and R₂ are hydrogen and R₃ represents methyl is, starting from phtalicanhydride (available on the market), a nine-steps synthesis among whichdifficult and poorly paying steps such as a substitution to an aromaticnucleus and a Hoffmann-rearrangement have to be carried out. Based onphtalic-anhydride the tricyclic starting material II is obtained in10-12% yield at most, whereas the yield of the tetracyclic final productI, dependent on the method chosen for closing ring D, is 3 to 10%.

When conducting an investigation into more convenient and well-yieldingmethods in preparing the tetracyclic compounds I, surprisingly a methodwas found which is based on a fully different concept as compared withthe conventional methods described before. The novel synthesisessentially comes to a closure of ring B instead of ring D in the finalstep of the synthesis.

The novel synthesis is very suitable for production on a large scale.The number of reaction steps required has been halved in regard to theconventional methods, whereas all reaction steps are well-paying andsimple chemical conversions.

The final step of the novel synthesis according to the invention ischaracterized by a ring closure of an intermediate product of thegeneral formula: ##STR4## or a salt thereof, in which n, m, R₁ R₂ and R₃have the meaning indicated above and X represents a hydroxyl group,halogen (Cl, Br or I) or an etherified or esterified hydroxyl group.

This reaction is performed in a dehydrating or, where X= halogen,dehydrohalogenating medium, preferably at a raised temperature.Dehydrating or dehydrohalogenating agents which are to be added to thereaction mixture for this purpose are i.a. acids such as H₂ SO₄,concentrated hydrochloride, picric acid, trifluoroacetic acid,phosphoric acid, polyphosphoric acid (PPA), phosphorous oxychloride,phosphorus trioxide or phosphorus pentoxide and Lewis acids(electrophilic agents) such as aluminum chloride, zinc chloride, tinchloride, titanium chloride or boron-trifluoride.

Preferred dehydrating agents are: sulphuric acid, phosphoric acid orderivatives of phosphoric acid, such as phosphorpentoxide andparticularly PPA. Aluminum chloride is the preferred dehydrohalogenatingagent.

The condensation described above, particularly the ring closure ofcompounds III, in which X represents a hydroxyl group, affords a veryhigh yield and proceeds almost quantitatively in the case of using astarting compound III, in which n= 1 and m= 2.

The intermediate compounds III, in which n= 1 and m= 2, are novelcompounds which can be prepared in a surprisingly simple manner byreaction of a compound of the general formula IV: ##STR5## or a saltthereof in which R₂ and R₃ have the aforesaid meanings and halrepresents halogen, preferably chlorine or bromine,

with an aniline derivative of the general formula: ##STR6## or a saltthereof in which R₁ and X have the aforesaid meanings.

This condensation of compound IV with compound V is carried out in asuitable solvent, preferably at a raised temperature.

A compound V, in which X stands for halogen, should preferably not beused in this condensation because under the reaction conditions requireda molecule V (X= halogen) will react with another molecule V (X=halogen) rather than with the compound IV, obviously resulting intolower yields. A compound of the general formula III in which Xrepresents halogen, is therefore preferably prepared by halogenating thecorresponding compound III in which X represents a hydroxyl group.

The excellent yields obtained in reacting a compound IV with a compoundV in which X stands for a hydroxyl group, is surprising and unexpected.The reactivity of derivatives of benzyl alcohol towards the usualalkylating agents is generally known, so that an alkalation of thehydroxyl group (X) of compound V was more likely.

The compound IV required may be prepared in various manners, forinstance starting from products available on the market such as styrene,styrene oxide or mandelic acid.

Thus a compound IV may, for example, be prepared by reacting styreneoxide or a styrene oxide derivative, which has been substituted (R₂) atthe phenyl nucleus, with the compound HNR₃₋₋ CH₂₋₋ CH₂₋₋ Z, in which R₃has the aforesaid meanings and Z represents a hydroxyl group or halogenfollowed by halogenating the hydroxy group(s) of the product thusobtained. Another manner consists of the reaction of aβ-halo-phenylethylamine derivative or a β-hydroxy-phenylethylaminederivative with dihaloethane or 1-hydroxy-2-halo-ethane, followed byhalogenating the hydroxyl group(s), possibly present, of the compoundthus obtained.

The preferred synthesis for the preparation of a compound IV is themethod in which a β-hydroxy-phenylethylamine derivative of the formulaVI: ##STR7## in which R₂ and R₃ have the aforesaid meanings, is reactedwith ethylene-oxide, after which the hydroxyl groups of the productobtained are halogenated in the usual manner, e.g. with SOCl₂, PBr₃,etc.

The compound VI is, for example, obtained directly by reactingstyrene-oxide with a primary amine (H₂ NR₃) or indirectly from mandelicacid by converting the acid into the desired amide and reducing theamide obtained into the corresponding amine.

The intermediate compounds III, in which n= 2 and m= 1 are also novelcompounds. These compounds III as well as the compounds III with n= 1and m= 2 may be prepared directly by reacting a compound of the generalformula VII: ##STR8## or a salt thereof, in which n, R₁ , R₂ and R₃ havethe aforesaid meaning and Y has the same meaning as X defined beforeexcept for halogen,

with reagents such as (an aqueous solution of) formaldehyde (m=1),methylene halide (m=1) or ethylene halide (m=2). Obviously thiscondensation reaction may also be performed with reagents containing anoxo group, such as phosgene (m= 1), alkylhaloformate (m= 1), dialkylcarbonate (m= 1), monohalo acetyl halide (m= 2), dialkyloxalate (m= 2),etc. The oxo group(s) in the condensation product thus obtained must,however, additionally be reduced to obtain the desired compound III. Forthese condensation reactions is referred to the Dutch Pat. No. 129,434and the Dutch patent application No. 72,12,915 in which suchcondensation reactions have been described for the formation of theD-ring, starting from tricyclic starting substances.

If the compound VII is used for preparing compounds III, a compound IIIin which X= halogen, is obtained by halogenating the correspondingcompound III, in which X= 30 hydroxy.

The, as far as known, novel compounds of the general formula VII may beprepared in a simple manner by reacting a compound of the formula VIII:##STR9## or a salt thereof, in which n, R₂ and R₃ have the aforesaidmeanings and hal represents halogen, preferably chlorine or bromine,

with an aniline derivative of the general formula IX: ##STR10## or asalt thereof, in which R₁ and Y have the aforesaid meanings.

The compound VIII required may be prepared in various manners startingfrom products available on the market such as styrene, styrene-oxide,mandelic acid, cinnamic acid or benzoyl acetic acid. Thus the compoundVIII, for example, may be prepared from β-hydroxy-phenylethylamine(directly available from styrene oxide) or fromγ-hydroxyphenylpropylamine (to be prepared in 2 steps fromethylbenzoylacetate or in 3 steps from cinnamic acid) by halogenation ofthe hydroxyl group.

The methods according to the present invention are further explained inthe attached flow sheet.

It is self-evident that the present novel method for the preparation ofthe compounds I is not restricted to that sequence of reaction steps andto those reagents which are indicated in the flow sheet. In specialcases, dependent on the final compound I that is to be prepared and onthe starting products that are available, it is very well possible toperform the reaction steps in another sequence or to use other reagentswhich, whether or not followed by an additional chemical reaction, havethe same result as indicated in the reaction scheme.

The reaction routes mentioned above for the preparation of the compoundsI mean a considerable reduction of time in comparison with theconventional methods. This particularly applies to the reaction routeindicated on the left side of the attached flow sheet for preparingcompounds I with n= 1 and m= 2. Instead of the 10 to 11 reaction stepsstarting from phtalic acid anhydride, the compound I (R₁, R₂ = H, R₃ =CH₃, n= 1, m= 2) may now be prepared in 4 or 5 steps starting fromexample from styrene oxide, which is obtainable on the market in largequantities. Thanks to the relatively simple chemical reactions which areapplied in the novel synthesis, the yield in comparison with theconventional method of preparation, has been improved by at least 300 to400%.

The compounds I have an asymmetric carbon so that they can be obtainedas racemic mixtures or as optically active compounds. The opticallyactive compounds I may be prepared by resolution of the racemiccompounds I. However, these enantiomers I may also be prepared in adirect way by carrying out the resolution in an earlier stage of the thesynthesis, for instance, on the compounds with formulae III or VII.

With salts in the present invention are meant the pharmaceuticallyacceptable acid addition salts obtained by reaction of the free base Iwith an anorganic or organic acid, such as hydrochloric acid, sulphuricacid, acetic acid, maleic acid, fumaric acid, citric acid, ascorbicacid, etc. Pharmaceutically acceptable quaternary ammonium salts,particularly the (1-4 C) alkyl ammonium salts, are obtained by reactionof the free base I with an alkylhaldide, preferably methyliodide. Thelatter salts have a marked antihistamine and antiserotonine activity.

In the examples the following nomenclature and numbering with regard tothe final products according to formula I has been used: ##STR11##

EXAMPLE I Preparation of 2(N)-methyl-1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrazino(1,2-a)-azepine, HCl salt and iodomethylate

1. 1(N)[(0-hydroxymethyl)-phenyl]-2-phenyl-4(N')-methylpiperazine.

To 2.3 g of β-chloro-N-methyl-N-chloroethyl-phenylethylamine in 2 ml ofdry dimethylformamide a solution of 1.23 g of 0-amino-benzylalcohol in 3ml of dimethylformamide is added dropwise at room temperature. Thismixture is stirred for half an hour at room temperature. Then 0.8 ml ofpyridine is added and the mixture heated to about 70°-80° C. Afterstirring for half an hour at this temperature, the mixture is cooleddown, added to water and the aqueous mixture washed with ether. Theaqueous solution is then made alkaline with the aid of sodium carbonateand after the extracted with ether. The ether extracts obtained arewashed with water (to neutral) dried and evaporated.

Yield: 2.1 g (75%); melting point 90°-95° C.

Rf in benzene: ethylalcohol (9:1)= 0.29.

2.2(N)-methyl-1,2,3,4,10,14-b-hexahydro-dibenzo(c,f)-pyrazino(1,2-a)-azepine.

2 g of the product obtained in 1. and 20 g of polyphosphoric acid (PPA)are heated for 1 hour at 100° C. After cooling down the mixture it ispoured into ice-water and then extracted with ether. The ethereal layeris washed with water to neutral and subsequently dried and evaporated todryness.

Yield: 1.8 g (100%); melting point 95°-100° C.

Melting point iodomethylate 285°-289° C.

Melting point HCl salt 264°-267° C. (dec.).

3. By halogenating the hydroxyl group of the compound obtained in (1)with thionylchloride the corresponding chloro-compound is obtained. Thischloro-compound is converted into the final product obtained in (2) inthe manner as specified in (2) but in the presence of AlCl₃ instead ofpolyphosphporic acid. The total yield via both steps is about 60%.

The same compound is prepared by esterifying the hydroxyl group of thecompound obtained in (1) with acetic acid and treating the acetoxycompound thus obtained in the manner as specified in (2) Total yield65%.

The starting product required in (1) may be prepared in the followingmanner:

A.1. preparation of β-hydroxy-N-methyl-N-hydroxyethylphenylethylamine(direct)

To 61 g of 2-methylaminoethanol in 70 ml of water are added dropwise 65g of styrene oxide in such a manner that the temperature does not riseabout 45° C. The mixture is then heated on a water bath for about 6hours after which the excess of 2-methylaminoethanol is distilled offunder reduced pressure (0.1 mm Hg). The oil obtained is dissolved in asmall quantity of benzene and then chromatographed on a silica-column(eluded with a mixture of ethyl alcohol:benzene (2:8), to which 2 dropsof concentrated ammonia were added). After evaporating the solvent alight-brown coloured oil is obtained.

(N_(D) ²⁰ = 1,5365). Yield about 75%.

A.2. preparation of β-hydroxy-N-methyl-N-hydroxyethylphenylethylamine(indirect)

a. To an aqueous solution of methylamine (72 ml; 40% solution) and 100ml of ethanol are added dropwise 24 g of styrene oxide. The mixture isstirred for 3 hours at room temperature. Subsequently the solvents areevaporated and the residue distilled at a reduced pressure (0.2 mm Hg at80°-85° C.). Treatment of the oil obtained with pentane yields acrystalline substance.

Melting point β-hydroxy-N-methylphenylethylamine 65°-70° C. Yield 65%.

b. A solution of 75 g of the product obtained in a. and 26 g of ethyleneoxide in 50 ml of absolute ethanol is heated for 18 hours at 60° C.After that the solvent is evaporated at reduced pressure and the oilyresidue chromatographed on a silica column (eluted with a mixture ofbenzene:ethyl-alcohol (1:1) to which 2 drops ammonia have been added.

After evaporation of the solvent a light-brown coloured oil is obtained(yield about 90%).

Rf in ethylalcohol:ammonia (9:1)= 0.67 on SiO₂.

(N_(D) ²⁰ 1.5363).

b. preparation of β-chloro-N-methyl-N-chloroethyl-phenylethylamine

To a solution of 20 g of the product obtained in (A) in 60 ml chloroforma solution of 40 ml thionylchloride in 60 ml of chloroform is addeddropwise at 0° C.

While stirring the mixture is heated at 60° C. for half an hour.Subsequently the solvent and the excess of thionylchloride are distilledoff. The residue, added to ice water, is washed with ether three timesand then made alkaline with the aid or sodium carbonate. The mixture isthen extracted with ether and the ether extracts washed with water toneutral and dried. After evaporation of the ether a yellow coloured oilis obtained which without any additional purification is used forfurther conversion.

Yield about 75%. N_(D) ²⁶ = 1.5291.

EXAMPLE II

In a similar manner the following compounds are prepared:

8-chloro-2(N)-methyl-1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrazino(1,2-a)-azepine.maleate;melting point 180°-185° C.,

1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrazino(1,2-a)-azepine.HCl;melting point 289°-291° C.,

8-methoxy-2(N)-methyl-1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrazino(1,2-a)-azepine.maleate;melting point 198°-199° C.,

2(n)-propyl-1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrazino(1,2-a)-azepine.maleate;melting point 214°-216° C.,

2(n),7-dimethyl-1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrazino(1,2-a)-azepine.maleate;melting point 230°-232° C.,

8-hydroxy-2(N)-methyl-1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrazino(1,2-a)-azepine.maleate;melting point 247°-250° C.,

2(n)-cyclopropylmethyl-1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrazino(1,2-a)-azepine.maleate; melting point 210°-213° C.,

2(n)-dimethylaminoethyl-1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrazino(1,2-a)-azepine.dimaleate; melting point 137°-139° C.(dec.),

2(N)-α-pyridinoethyl-1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrazino(1,2-a)-azepine.2HCl; melting point 238°-242° C.,

8-bromo-2(N)-methyl-1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrazino(1,2-a)-azepine.maleate;melting point 188°-191° C.,

13-methyl-(2(N)-methyl-1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pryazino(1,2-a)-azepine.HCl;melting point 275° C. (dec.),

13-chloro-2(N)-methyl-1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrazino(1,2-a)-azepine;melting point 123°-125° C.,

11-methoxy-2(N)-methyl-1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrazino(1,2-a)-azepine.maleate;melting point 189°-194° C.,

13-methoxy-2(N)-methyl-1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrazino(1,2-a)-azepine.HCl;melting point 270°-272° C.,

2(n)-ethyl-1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrazino(1,2-a)-azepine.HCl;melting point 280°-286° C.,

12-chloro-2(N)-methyl-1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrazino(1,2-a)-azepine.HCl;melting point >290° C.

EXAMPLE III 1. β-[(O-hydroxymethyl)-anilino]-N-methylphenylethylamine

To a solution of 12.3 g of O-amino-benzylalcohol in 100 ml ethanol:water(95:5) and 16 g pyridine (0.2 mol) is added dropwise a solution of 20.6g of β-chloro-N-methylphenylethylamine.HCl in 100 ml ethanol:water(95:5). The mixture is then refluxed for 12 hours. The mixture is thencooled down, after which the solvent is evaporated. The residue ispoured in water and washed with ether three times. The water layer ismade alkaline with 2N sodium hydroxide and subsequently extracted withether three times. The ether extracts are washed with water, dried andevaporated. The residue is used without any additional purification.

Rf in alcohol:toluene (1:9)= 0.55 on SiO₂.

2. 1(N)-[(O-hydroxymethyl)-phenyl]-2-phenyl-4(N')-methylpiperazine

To 400 ml of 1,2-dibromoethane at 100° C. is added drop-wise a solutionof 10 g of the product obtained in (1) in 30 ml of pyridine after whichthe mixture is left stand at this temperature for 20 minutes.

Then pyridine and the excess of dibromoethane are distilled off in vacuoafter which the residue is poured into water and washed with ether.Subsequently the water layer is made alkaline with sodiumcarbonate andextracted with ether.

The ether layer is washed with water, dried and evaporated. Meltingpoint 90°-94° C. Yield 60%.

The same product is obtained by reacting the compound obtained in (1)with ethylchloroacetate or diethyl oxalate and reducing the mono- ordi-oxo-compound thus obtained with LiAlH₄.

3.2(N)-methyl-1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrazino(1,2-a)-azepine

In the manner as in example (I.2.) the product obtained in (2) isconverted into the final product mentioned above.

Melting point 96°-100° C. Yield 95%. Melting point of the HCl salt 265°C.

EXAMPLE IV

In a similar manner as indicated in example III the following compoundsare prepared:

8-methoxy-2(N)-methyl-1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrazino(1,2-a)-azepine.maleate;melting point 196°-199° C.,

2(n)-propyl-1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrazino(1,2-a)-azepine.maleate;melting point 212°-215° C.

EXAMPLE V γ-chloro-N-methyl-phenylpropylamine

To a cooled suspension of 20 g ofγ-hydroxy-N-methylphenylpropylamine.HCl in chloroform are added dropwise30 ml of thionylchloride. The mixture is subsequently stirred at roomtemperature till all solid substance has been dissolved. The solventchloroform and the excess of thionylchloride are distilled off afterwhich the residue is washed with ether and then made alkaline (pH= 8)with a sodiumcarbonate solution (10%). The alkaline solution issubsequently extracted with ether and the ether extracts washed withwater, dried and evaporated to dryness. The residue (oil) is usedwithout any additional purification (yield 15.6 g; 85%).

2. γ[(O-hydroxymethyl)-anilino]-N-methyl-phenylpropylamine

In the same way as described in example (III.1) 13.8 g of the oilobtained in (1) are reacted with O-amino-benzyl-alcohol dissolved inethanol:water (95:5) to which 6 g of pyridine have been added. Theproduct obtained (a yellow coloured oil) is further converted withoutany purification.

Rf in ethylalcohol:toluene (1:9)= 0.5. Yield 70% (14.1 g).

3.3(N)-[(O-hydroxymethyl)-phenyl]-4-phenyl-1(N)-methylhexahydropyrimidine

A solution of 13.5 g of the oil obtained in (2) in an aqueousformaldehyde solution is stirred for 1.5 hours at about 75° C.

Subsequently the mixture is diluted with water and extracted with etherthree times. The ether extracts are washed, dried and evaporated todryness. The oily residue (13.4 g, 95%) is used without furtherpurification.

The same product is obtained if methylenechloride, dissolved indimethylsulfoxide to which some drops of triethylamine have been added,is used instead of the aforesaid aqueous formaldehyde-solution. The sameproduct is also obtained by using ethylchloroformate instead ofmethylene chloride and reducing the oxo-compound thus obtained withLiAlH₄.

4.3(N)-methyl-1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrimidino(3,4-a)-azepine

In a similar manner as indicated in example (I.2) the product obtainedin 3. is converted into the above-mentioned final product.

Yield (oil) 75%. Melting point fumarate 188°-191° C. (dec.).

EXAMPLE VI

In a similar manner as described in example V the following compoundsare prepared:

1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrimidino(3,4-a)-azepine.HCl;melting point 212°-217° C.,

3(n)-methyl-7-trifluoromethyl-1,2,3,4,10,14b-hexahydrodibenzo(c,f)-pyrimidino(3,4-a)-azepine,

(-)3(N)-methyl-1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrimidino(3,4-a)-azepine.fumarate;melting point 185°-188° C., [α]_(D) ²⁰ = -333°,

(+)3(n)-methyl-1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrimidino(3,4-a)-azepine.fumarate;melting point 184°-187° C., [α _(D) ²⁰ = +335°,

3(n)-ethyl-1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrimidino(3,4-a)-azepine.HCl; melting point 198°-201° C.

EXAMPLE VII 2(N)-methyl-1,2,3,4,10,14b-hexahydro-dibenzo(c,f)-pyrazino(1,2-a)-azepine

1 g of 1(N)[(O-hydroxymethyl)-phenyl]-2-phenyl-4(N')-methyl-piperazineis added in small portions, while stirring, to 3 ml of concentratedsulphuric acid at room temperature.

The reaction is strongly exothermic so that the mixture has to be cooleda little to keep the mixture at ambient temperature.

The mixture is then stirred for another two hours and subsequentlypoured in ice-water. The aqueous mixture is made alkaline withconcentrated ammonia, after which it is extracted with ether. The etherlayers are washed, dried and evaporated to dryness.

Melting point 90°-95° C. Yield 90%.

I claim:
 1. Process for the preparation of a compound of the formula:inwhich n is the number 1 or 2, m is the number 1 if n= 2, and the number2 if n= 1, R₁ and R₂ are selected from the group consisting of hydrogen,hydroxy, halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4carbon atoms, and trifluoromethyl, R₃ is selected from the groupconsisting of hydrogen and alkyl having 1 to 6 carbon atoms,whichcomprises ring-closing a compound of the formula: ##STR13## or a saltthereof, in which n, m, R₁, R₂ and R₃ have the aforesaid meanings, and Xis selected from the group consisting of hydroxy, chlorine, bromine,iodine and esterified hydroxy, in the presence of an acid or a Lewisacid and recovering the desired compound from the reaction mixture. 2.The process according to claim 1 in which a compound of formula III isused in which X represents a hydroxy group.
 3. Process according toclaim 1 in which the ring closure is carried out in the presence of amember of the group consisting of polyphosphoric acid, phosphorustrioxide, and phosphorus pentoxide.
 4. The process according to claim 1in which the esterified hydroxy group is acetoxy.